Lack of stimulatory effect of dienogest on the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by endothelial cell as compared with other synthetic progestins.

Abstract

OBJECTIVES:

Monocyte adhesion to endothelial cells is an important initial event at the onset of atherosclerosis. It is partially mediated by the expression of adhesion molecules on the endothelial cell surface. While estrogens inhibit the development of atherosclerosis, the effect of co-administered progestin remains controversial. We examined the effect of progestins on cytokine-stimulated human umbilical venous endothelial cell (HUVEC) expression of adhesion molecules.

METHODS:

In HUVECs, mRNA expression of progesterone receptors (PRs) and androgen receptors (AR) was determined by RT-PCR. HUVECs were stimulated by interleukin-1beta (IL-1beta) for 24 h with or without various steroids, and then the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was semiquantified by ELISA.

RESULTS:

In all preparations of HUVECs used in this study, RT-PCR confirmed mRNA expression of both isoforms of PR, PR-A and PR-B, as well as AR. Addition of progesterone (10(-10)-10(-7) M) or dienogest (DNG) (10(-10)-10(-8) M) did not affect IL-1beta-stimulated ICAM-1 or VCAM-1 expression. In contrast, medroxyprogesterone acetate, norethindrone acetate and levonorgestrel (10(-10)-10(-8) M) dose-dependently increased cell adhesion molecules. The progestin-induced increase was blocked by the concomitant addition of mifepristone, a PR antagonist, but not by hydroxyflutamide, an AR antagonist, indicating that the progestin stimulation was mediated predominantly via PR.

CONCLUSIONS:

These results suggest that DNG, unlike other synthetic progestins, lacks stimulation of cell adhesion molecules. For the prevention of atherosclerosis, estrogen in combination with DNG may be a suitable regimen in hormone replacement therapy in postmenopausal women.

• Authors: Hiroshi Tatsumi, Jo Kitawaki, Kazunori Tanaka, Tetsuya Hosoda, Hideo Honjo
• Journal: Maturitas (Maturitas) Vol. 42 Issue 4 Pg. 287-94 (Aug 30 2002) ISSN: 0378-5122 [Print] Ireland
• PMID: 12191851 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Elsevier Science Ireland Ltd.

Chemical References

• Interleukin-1
• Progesterone Congeners
• Receptors, Androgen
• Receptors, Progesterone
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• dienogest
• Levonorgestrel
• Nandrolone
• Norethindrone Acetate
• Medroxyprogesterone Acetate
• Norethindrone

Topics

• Arteriosclerosis (prevention & control)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Intercellular Adhesion Molecule-1 (biosynthesis)
• Interleukin-1 (pharmacology)
• Levonorgestrel (pharmacology)
• Medroxyprogesterone Acetate (pharmacology)
• Nandrolone (analogs & derivatives, pharmacology)
• Norethindrone (analogs & derivatives, pharmacology)
• Norethindrone Acetate
• Progesterone Congeners (pharmacology)
• Receptors, Androgen (metabolism)
• Receptors, Progesterone (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Umbilical Veins
• Vascular Cell Adhesion Molecule-1 (biosynthesis)